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Beta-Blockers to Reduce Mortality in Patients with Systolic Dysfunction.

A Meta-Analysis

* OBJECTIVE We reviewed published clinical trials and performed a meta-analysis to assess if therapy with adrenergic [Beta]-antagonists ([Beta]-blockers) reduces the risk of mortality in patients with systolic dysfunction.

* STUDY DESIGN A systematic review was performed with meta-analysis where appropriate. We reviewed clinical trials with respect to the quality of the research methods, including patient population and end points. Two independent reviewers calculated relative risk, relative risk reduction, absolute risk reduction, and number needed to treat for the total mortality end point reported in each trial. A meta-analysis was performed.

* DATA SOURCES We searched pertinent indexing services and references from published articles for relevant literature. The selected clinical trials were randomized, double-blinded, and controlled, and included patients with systolic heart failure. Mortality was assessed as a primary or secondary end point.

* OUTCOMES MEASURED The primary outcome was mortality.

* RESULTS Statistically and clinically significant improvement, including a statistically significant reduction in mortality, has been noted in patients receiving therapy with either bisoprolol, carvedilol, or metoprolol. Pooled analysis revealed a statistically significant reduction in the risk of total mortality (odds ratio [[OR].sub.MH]=0.66; 95% confidence interval [CI], 0.58-0.75) and sudden death ([OR.sub.MH]=0.61; 95% CI, 0.5-0.75) for patients receiving [Beta]-blocker therapy.

* CONCLUSIONS All patients with New York Heart Association class II and III heart failure should receive [Beta]-blocker therapy with bisoprolol, carvedilol, or metoprolol. Additional clinical trials are ongoing and will provide further data on which patients receive the greatest benefit from therapy and which [Beta]-blocker may be preferred.

* KEYWORDS Heart failure, congestive; cardiomyopathy, congestive; adrenergic beta-antagonism. (J Fam Pract 2001; 50:499-504)

The annual mortality in patients with mildly symptomatic heart failure ranges from 5% to 10%. However, as symptoms progress in severity, annual mortality may reach 30% to 40%.[1] Mortality remains high in patients maintained on standard therapy (including an angiotensin-converting enzyme [ACE] inhibitor[1,2]) in large part because of the impact of sudden cardiac death in patients with heart failure.[3] Additional therapeutic agents are needed to improve survival for this patient population.[1,3]

Heart failure may be associated with either systolic or diastolic dysfunction. Patients with systolic dysfunction have poor left ventricular wall motion and an ejection fraction of less than 40%. Patients with diastolic dysfunction have a normal ejection fraction but a noncompliant left ventricular wall that impairs diastolic filling. The etiology of heart failure may be ischemic or nonischemic.[1] Coronary artery disease[1,4] and hypertension are common etiologic factors.[1]

Beta-blocker therapy results in an acute negative inotropic effect.[5] This acute effect led to the conventional belief that [Beta]-blockers were contraindicated in patients with heart failure.[2,4] However, clinical trials have demonstrated beneficial effects of long-term [Beta]-blockade in patients with heart failure, including improvements in clinical status,[6] heart failure symptoms,[1] ventricular function,[5] disease progression,[7,8] and hospitalization.[8-12] As a result of the identification of these beneficial effects, clinical trials have been conducted to assess the impact of [Beta]-blocker therapy on mortality.[3,4,9,11-15] Our goal for this systematic review was to synthesize available data and determine whether [Beta]-blocker therapy reduces the risk of mortality in patients with systolic dysfunction.

METHODS

Literature Search

Two independent searches of MEDLINE (1966 to February 2000) were conducted to identify published randomized double-blind controlled trials of [Beta]-blockers in patients with chronic heart failure. We used both Medical Subject Heading (MESH) terms and key words to provide a broad search. The results were limited to English language articles involving human subjects and the publication type "clinical trial." In addition to MEDLINE, we searched several other databases for relevant literature, including International Pharmaceutical Abstracts, Iowa Drug Information Service, Current Contents, and The Cochrane Library. We examined references from published clinical trials and reviewed articles to identify further potential articles for inclusion in our evaluation. Finally, the manufacturers of metoprolol (Novartis Pharmaceuticals Corporation, East Hanover, NJ), carvedilol (SmithKline Beecham Pharmaceuticals, Philadelphia, Pa), and bisoprolol (Lederle Laboratories, Philadelphia, Pa) were contacted in an effort to ensure that pertinent articles were identified and included.

We determined the criteria for inclusion before conducting the literature searches. Clinical trials were included if they were randomized, double-blinded, and controlled; if the patients had a diagnosis of systolic heart failure; and if they assessed mortality as a primary or secondary end point. They were excluded if the study duration was shorter than 3 months or if publication occurred before 1975.

We examined 280 articles or abstracts for our review. Although several clinical trials were not included because of study design issues (eg, lack of randomization or blinding), the majority (approximately 95%) were excluded because they lacked a mortality end point. None of the identified trials used an active comparator; therefore, all trials were placebo controlled. Ultimately, we identified 6 clinical trials[3,9,11-14] meeting the criteria and used them in our analysis.

Quality Assessment

Each study was evaluated using the instrument designed by Jadad and colleagues[16] that rates study quality from 0 (worst) to 5 (best). Two of the 6 clinical trials identified received a score of 5,[11,14] while the remaining 4 received a score of 4.[3,9,12,13] The reasons for lower scores included a lack of description of the randomization process[13] or of which patients withdrew from the trials?[3,9,12]

Analysis of Data

We critically analyzed the mortality end points of each study. Two independent reviewers calculated relative risk, relative risk reduction (RRR), absolute risk reduction, and number needed to treat (NNT) for total mortality. The NNT is a numerical representation of the number of patients that must be treated to prevent 1 adverse outcome (in this case death) in the population studied for the duration of the trial. Direct comparisons of NNT between studies should be avoided; since the benefit cannot be assumed to have occurred in even increments throughout the trial, the NNT serves only as an alternate form of data presentation. The results of these 4 calculations are provided in an effort to allow for additional assessment of the clinical trials evaluated.

Homogeneity of effect was assessed by calculating a Q statistic, where the number of degrees of freedom is equal to the number of trials included in the analysis minus 1. A P value of less than .05 was considered statistically significant. The pooled estimate of effect was calculated using the Mantel-Haenszel method, which assumes a fixed effect model. The variance of the individual risk assessments, the weight of each study, and ultimately the summary odds ratio (OR) and 95% confidence interval (CI) were calculated for mortality end points when studies were homogenous using this method as previously described.[17]

RESULTS

Study Characteristics

Of those identified, 2 trials each evaluated bisoprolol (the Cardiac Insufficiency Bisoprolol Study [CIBIS][11] and the Cardiac Insufficiency Bisoprolol Study II [CIBIS-II][12]), carvedilol (the Australia/New Zealand Heart Failure Research Collaborative Trial [ANZ][9] and the US Carvedilol Heart Failure Program [US Carvedilol][13]), and metoprolol (the Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure [MERIT-HF][3] and the Metoprolol in Dilated Cardiomyopathy [MDC][14] trial). A total of 9335 patients were enrolled in the 6 trials.[3,9,11-14] With an average 7.5% withdrawal rate during the active run-in phases,[9,13,14] 9171 patients were ultimately randomized to receive either [Beta]-blocker or placebo therapy. The average withdrawal rate after randomization was 15.8% for patients receiving active treatment compared with 17.2% for patients receiving placebo (P [is greater than] .05 for each individual trial).[3,9,11-14]

Patient Characteristics

There were no statistically significant differences between the baseline characteristics of the patients receiving active treatment versus placebo. The mean age of patients was 60 years, with an average of 78% men. All patients were receiving pharmacologic treatment for their heart failure before study enrollment. Although the studies used various ejection fraction requirements, the average ejection fraction ranged from 22% to 29%.[3,9,11-14] In all studies the majority of patients had New York Heart Association (NYHA) class II or III heart failure.[3,9,11-14] Table 1 shows the study characteristics for each included clinical trial and the baseline characteristics of enrolled patients.
TABLE 1
STUDY AND PATIENT CHARACTERISTICS

                                              Bisoprolol

                                        CIBIS[11]    CIBIS[12]

                                         B     P      B     P

Total randomized,(*)                       641          2647
Heart failure etiology, %
Ischemic                                 56    53     50    50
Nonischemic                              44    47     50    50
Mean baseline resting heart rate, bpm    83    83     80    81
Mean baseline SBP, mm Hg                128   126    129   130
Mean baseline DBP, mm Hg                 80    78     79    80
Target dose                                5 mg        10 mg
                                        once daily   once daily
Patients receiving target dose, %           59           43
Mean follow-up, years                      1.9          1.3

                                              Carvedilol
                                                         US
                                           ANZ[9]     Carvedilol[13]

                                         C     P       C     P

Total randomized,(*)                       415          1094
Heart failure etiology, %
Ischemic                                100   100      48    47
Nonischemic                               0     0      52    52
Mean baseline resting heart rate, bpm    NR    84      83    90
Mean baseline SBP, mm Hg                 NR   116     115   118
Mean baseline DBP, mm Hg                 NR    72      73    NR
Target dose                                25 mg      25-50 mg
                                        twice daily   twice daily
Patients receiving target dose, %           48            80
Mean follow-up, years                      1.6        0.54 (median)

                                              Metoprolol

                                          MDC[14]    MERIT-HF[3]

                                         M     P      M    P

Total randomized,(*)                       383         3991
Heart failure etiology, %
Ischemic                                  0     0     65   66
Nonischemic                             100   100     35   34
Mean baseline resting heart rate, bpm    91    82
Mean baseline SBP, mm Hg                118   130
Mean baseline DBP, mm Hg                 78    78
Target dose                             100-150 mg   200 mg
                                        once daily   once daily
Patients receiving target dose, %           NR            64
Mean follow-up, years                       1.2          1.0

NOTE: All numbers have been rounded to the nearest whole number.

(*) Accounting For withdrawal during run-in phase where applicable.
C denotes carvedilol; P, placebo; B, bisoprolol; M, metoprolol;
N, number of patients; bpm, beats per minute; SBP, systolic blood
DBP, diastolic blood pressure: mm Hg, millimeters of mercury; NR, data
not reported.


End Points

Mortality offers an objective and clear end point for clinical trials. It supersedes other safety and efficacy end points.[1] Table 2 provides a summary of selected mortality end points and the notation of the statistical significance of the end point in each trial. The calculated risk reduction demonstrated for total mortality in trials generating a statistically significant mortality benefit is given.
TABLE 2
SELECTED MORTALITY END POINTS

                                    Bisoprolol

                           CIBIS[11]             CIBIS-II[12]

                       B      P     Result    B      P     Result

Total mortality, %    16.6   20.9     NS     11.8    7.3     S

Relative risk
reduction,(*) %          3     59     32

Absolute risk
reduction              5.5   4.6     3.5

Number needed to
treat([dagger])         18     22     29

Sudden death,
([double dagger]) %    5.9   7.5      NS      3.6    6.3     S

Cardiovascular
death, %              12.5   18.4     NS      9.0   12.2     S

                                    Carvedilol

                           ANZ[9]            US Carvedilol[13]

                       C     P     Result    C     P    Result

Total mortality, %    9.6   12.6     NS     3.2   7.8     S

Relative risk
reduction,(*) %

Absolute risk
reduction

Number needed to
treat([dagger])

Sudden death,
([double dagger]) %    NR    1.7    3.8      NS   6.3    9.3

Cardiovascular
death, %              8.7    9.7     NS     2.9   7.8      S

                                   Metoprolol

                           MDC[14]              MERIT-HF[3]

                       M      P     Result   M      P     Result

Total mortality, %    11.9   10.1     NS     7.3   10.8     S

Relative risk
reduction,(*) %

Absolute risk
reduction

Number needed to
treat([dagger])

Sudden death,
([double dagger]) %     NS    4.0    6.6       S

Cardiovascular
death, %               9.5   11.9     NS     6.4   10.1     S

NOTE: Result refers to the outcome of comparison between the treatment
and control group for the study and end point noted.
B denotes bisoprolol; C, carvedilol; M, metoprolol; P, placebo;
NR, not reported; NS, not statistically significant; S,
statistically significant.

(*) Risk reductions represent therapy with a [Beta]-blocker
compared with placebo.

([dagger]) Number needed to treat represents the number of patients
that need to be treated with the [Beta]-blocker for the length of
the study to prevent the occurrence of one death (Table 1).

([double dagger]) Sudden death or death known to be due to
ventricular tachycardia or ventricular fibrillation.


A statistically and clinically significant decrease in mortality was reported in CIBIS-II, US Carvedilol, and MERIT-HF. These clinical trials included a total of 7732 patients receiving 1 of 3 different [Beta]-blockers.[3,12,13] A nonsignificant reduction in total mortality was noted in patients receiving [Beta]-blocker therapy in CIBIS-I and ANZ,[9,11] while a nonsignificant increase in total mortality was reported in patients receiving [Beta]-blocker therapy in the MDC trial.[14] These clinical trials included a total of 1439 patients and were not powered to assess this end point.[9,11,14]

Analysis revealed that the 6 clinical trials are homogenous in total mortality (Q=9.3). This indicates that the trials are measuring an effect of the same size and that differences in issues such as study design and patient population would not be expected to have an appreciable impact on the outcome of meta-analysis. When the results of all 6 trials were pooled, a statistically significant reduction in the risk of total mortality was noted ([OR.sub.MH]=0.66; 95% CI, 0.58-0.75). The Figure is a representation of the effect of [Beta]-blocker therapy on total mortality.
FIGURE
EFFECT OF B-BLOCKER THERAPY ON TOTAL MORTALITY

[ILLUSTRATION OMITTED]

Clinical Trial      [Beta]-Blocker   Placebo

                        (Number of deaths/
                         number at risk)

CIBIS[11]              53/320         67/321
CIBIS-II[12]          156/1327       228/1320
ANZ[9]                 20/208         26/207
US Carvedilol[13]      22/696         31/398
MDC[14]                23/194         19/189
MERIT-HF[3]           145/1990       217/2001
Overall                 --             --

CIBIS denotes Cardiac Insufficiency Bisoprolol Study; CIBIS-II, Cardiac
Insufficiency Bisoprolol Study II; ANZ, Australia/New Zealand Heart
Failure Research Collaborative Trial; US Carvedilol, US Carvedilol
Heart Failure Program; MDC, Metoprolol in Dilated Cardiomyopathy trial;
MERIT-HF, Metoprolol CR/XL Randomised Intervention Trial in Congestive
Heart


Five of the 6 trials reported mortality caused by sudden death.[3,11-14] Both MERIT-HF and CIBIS-II reported significant decreases in sudden death in patients receiving [Beta]-blocker therapy.[3,12] Of the remaining 3 studies, the MDC trial showed a nonsignificant increase in sudden death,[14] and CIBIS and US Carvedilol showed a nonsignificant decrease in sudden death.[11,13] US Carvedilol had a larger RRR with respect to sudden death than MERIT-HF or CIBIS-II; however, statistical significance was not reached.[13] Analysis revealed that these 5 trials were homogenous (Q=7.0) with respect to sudden death. When their results were pooled, a statistically significant reduction in the risk of sudden death was noted ([OR.sub.MH]=0.61; 95% CI, 0.5-0.75). All the included trials evaluated cardiovascular mortality as an end point; however, analysis revealed that the trials are heterogenous with respect to cardiovascular mortality (Q=12.7), and therefore a summary statistic would be misleading.

With analyses of the impact of disease severity and etiology of heart failure within the clinical trials, we attempted to determine the response of various subgroups to [Beta]-blocker therapy. Patients with NYHA class IV heart failure represented 3.6% and 17% of the MERIT-HF and CIBIS-II study populations, respectively. Subgroup analyses in these studies indicated that patients with NYHA class III heart failure had a nonsignificant but greater RRR in mortality than did those of NYHA class IV[3,12] and II heart failure.[3] US Carvedilol did not categorize patients according to NYHA class but rather stratified them on the basis of exercise test performance into mild, moderate, and severe categories. There was no difference in mortality benefit with [Beta]-blocker therapy between these 3 defined groups.[13]

The results of CIBIS-II, MERIT-HF, and US Carvedilol stratified by heart failure etiology indicated a decrease in mortality in patients with both ischemic and nonischemic heart failure. All 3 studies noted a significantly reduced mortality in patients with ischemic heart failure.[3,12,13] US Carvedilol demonstrated a statistically significant decrease in mortality in patients with nonischemic heart failure receiving [Beta]-blocker therapy,[13] while MERIT-HF and CIBIS-II did not.[3,12]

DISCUSSION

Our findings indicate that there is a significant reduction in the risk of total mortality in patients receiving [Beta]-blocker therapy. US Carvedilol reported the largest RRR in mortality with [Beta]-blocker therapy in patients with heart failure[13] compared with the other large trials that found a significant decrease in the risk of death.[3,12] The RRR noted with carvedilol therapy approaches twice that reported with bisoprolol or extended-release metoprolol, although the absolute risk reductions are similar. The shorter study period employed in US Carvedilol compared with the other trials may provide some explanation for the large benefit noted, especially if the benefit of [Beta]-blocker therapy in this patient population is maximized early in the course of therapy. Also, the active run-in phase resulted in the withdrawal of 8.6% of the patients before randomization. Eliminating patients intolerant to carvedilol may have created the appearance of an elevated response to therapy compared with that seen in trials that did not employ an active run-in phase. Moreover, the patients included in US Carvedilol had a lower mean ejection fraction and a greater prevalence of nonischemic heart failure than the other clinical trials reviewed. The most intriguing potential explanation for the apparent greater mortality benefit with carvedilol compared with bisoprolol or metoprolol is the additional pharmacologic effects associated with carvedilol. In addition to [[Beta].sub.1]-adrenergic blockade, carvedilol blocks [[Alpha].sub.1]-and [[Beta].sub.2]-adrenergic receptors and has antioxidant effects.[18] The contribution of these pharmacologic properties to the mortality benefit demonstrated with carvedilol therapy is currently unknown.

The limited number of patients with NYHA class IV heart failure enrolled in MERIT-HF make comparative benefit speculations unreliable. Also, the disease severity stratification used in US Carvedilol is not standardized, and the sample size representing the most severe patients was less than 10% of the study population. Based on the data currently available, it is not known if the magnitude of benefit with [Beta]-blocker therapy is related to disease severity.

The number of patients with nonischemic heart failure receiving [Beta]-blocker therapy was largest in MERIT-HF,[3] followed by US Carvedilol[13] and CIBIS-II.[12] Of these, US Carvedilol was the only trial to demonstrate a statistically significant decrease in mortality in patients with nonischemic heart failure receiving [Beta]-blocker therapy.[13] This may indicate that greater benefit can be derived with carvedilol than with bisoprolol or metoprolol therapy in patients with nonischemic heart failure. Further data are needed to fully assess the impact of heart failure etiology on mortality following [Beta]-blocker therapy.

Sudden death, which is often attributed to ventricular tachycardia or fibrillation,[19] is a major cause of mortality in patients with heart failure. Although large trials evaluating metoprolol and carvedilol reported a significant reduction in sudden death,[3,12] the use of concomitant antiarrhythmic medications varied between each trial evaluated. For example, approximately 15% of patients in CIBIS-II were receiving therapy with amiodarone,[12] which has been shown to decrease the occurrence of sudden death in patients with heart failure.[20] However, amiodarone therapy was evenly distributed between patients receiving bisoprolol and placebo12 and would not be expected to have a untoward effect on the assessment of sudden death.

Relative contraindications to [Beta]-blocker use are reflected in the exclusion criteria used in the trials discussed and include clinical instability,[3,11-13,14] second- or third-degree heart block in the absence of an implantable pacemaker,[3,9,13] low blood pressure,[3,9,12] low heart rate,[9,12,13] or treatment-requiring obstructive airway disease.[9,12,14] All the trials we reviewed indicated that [Beta]-blocker therapy in patients with heart failure does not result in a clinically significant decrease in systolic or diastolic blood pressure. As expected, however, a decrease in heart rate of approximately 10 to 15 beats per minute is likely to occur.[3,9,11-14] It is important to note that in US Carvedilol, increased dizziness in the carvedilol-treated patients was noted compared with placebo. Dizziness was most pronounced after a dosage increase and dissipated with continued use.[13] Target doses reached with [Beta]-blocker and placebo therapies were similar,[9,13,14] further confirming the tolerability of these agents with progressive dose titration.

Patients with Heart Failure

On the basis of studies reviewed, it is reasonable to anticipate a 15% to 20% withdrawal rate from [Beta]-blocker therapy in patients with systolic heart failure. The reasons for withdrawal will most commonly be worsening heart failure or side effects, such as fatigue and dyspnea. It is reassuring that the rates of withdrawal in the trials were similar for placebo and active therapies, suggesting that [Beta]-blocker therapy was not the primary cause of withdrawal.

Questions remain concerning the effects of [Beta]-blockade in patients with heart failure. The Carvedilol Prospective Randomized Cumulative Survival Trial was designed to evaluate the mortality effect of carvedilol versus placebo in patients with severe heart failure.[4,21,22] Although not published at the time of this review, the trial was discontinued early as a result of a large and consistent decrease in mortality in patients receiving carvedilol.[23] The Carvedilol ACE Inhibitors Remodeling Mild Heart Failure Evaluation trial is designed to evaluate carvedilol in asymptomatic patients with left ventricular dysfunction.[12,21] Also, the Beta-blocker Evaluation Survival Trial evaluated bucindilol versus placebo in patients with moderate to severe heart failure.[4,15,21] This trial was discontinued early because of lack of mortality benefit[24]

Heart failure primarily affects the elderly population older than 65 years.[1] Currently published trials have not included large numbers of elderly patients,[12,21,22] and therefore, extrapolation of the data to this patient population should be done with caution. Also, the effects of race and ethnicity have yet to be systematically addressed.[21] Studies designed to assess the impact of [Beta]-blockade in patients with heart failure depending on the etiology of their disease would allow for further maximization of benefit. The Carvedilol Post-Infarction Survival Control in Left Ventricular Dysfunction trial[22] was designed to evaluate patients with heart failure following an acute myocardial infarction.[12,22] Clinical trials are needed to determine optimal dosing regimens.[3]

Comparative clinical trials with a mortality end point have not been conducted. Efficacy comparisons between selective and nonselective [Beta]-blockers are necessary to quantify the survival benefit.[3] The Betaxolol Versus Carvedilol in Chronic Heart Failure study is designed to compare betaxolol with carvedilol in patients with NYHA class II or III heart failure.[4] The comparative efficacy of carvedilol with he [[Beta].sub.1]-selective agent metoprolol is being assessed in the Carvedilol and Metoprolol European Trial.[4,21,22]

CONCLUSIONS

All stable patients with NYHA class II and III heart failure should be considered for [Beta]-blocker therapy. Therapy should be initiated only in stable patients using a low dose of a [Beta]-blocker. This dose may be subsequently gradually titrated upward by doubling the current dose every 1 to 2 weeks on the basis of clinical response and patient tolerability.

KEY POINTS

* Beta-blocker therapy significantly reduces the risk of mortality in patients with heart failure.

* All stable patients with New York Heart Association class II and III heart failure should be considered for treatment with bisoprolol, carvedilol, or metoprolol.

* Therapy should be initiated at a low dose and titrated to an appropriate target based on clinical response and patient tolerance.

* Further studies are needed to determine the impact of patient factors (eg, age, race) and disease factors (eg, severity of heart failure, etiology of heart failure) on outcomes in patients with heart failure receiving [Beta]-blocker therapy.

ACKNOWLEDGMENTS

We would like to acknowledge the assistance of Deborah S. Carson, PharmD, BCPS, and Che Jordan, PharmD.

REFERENCES

[1.] Packer M, Cohn JN, eds. Consensus recommendations for the management of chronic heart failure. Am J Cardiol 1999; 83:1A-38A.

[2.] Doughty RN, MacMahon S, Sharpe N. Beta-blockers in heart failure: promising or proved? JACC 1994; 23:814-21.

[3.] MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomised intervention trial in congestive heart failure (MERIT-HF). Lancet 1999; 353:2001-07.

[4.] Bohler S, Saubadu S, Scheldewaert R, Figulla H. Betaxolol versus carvedilol in chronic heart failure (BETACAR study) rationale and design. Arzneim Forsch/Drug Res 1999; 49:311-17.

[5.] Bristow MR. Mechanism of action of beta-blocking agents in heart failure. Am J Cardiol 1997; 80:26L-40L

[6.] Colucci WS, Packer M, Bristow MR, et al. Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. Circulation 1996; 94:2800-06.

[7.] Bristow MR, Gilbert EM, Abraham WT, et al. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. Circulation 1996; 94:2807-16.

[8.] Packer M, Colucci WS, Sackner-Bernstein JD, et al. Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure. Circulation 1996; 94:2793-99.

[9.] MacMahon S, Sharpe N, Doughty R, Randomised, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease. Lancet 1997; 349:375-80.

[10.] Tsuyuki RT, Yusuf S, Touleau JL, et al. Combination neurohormonal blockade with ACE inhibitors, angiotensin II antagonists and [Beta]-blockers in patients with congestive heart failure: design of the randomized evaluation of strategies for left ventricular dysfunction (RESOLVED) Pilot Study. Can J Cardiol 1997; 13:1166-74.

[11.] CIBIS Investigators and Committees. A randomized trial of (-blockade in heart failure: the cardiac insufficiency bisoprolol study (CIBIS). Circulation 1994; 90:1765-73.

[12.] CIBIS-II Investigators and Committees. The cardiac insufficiency bisoprolol study II (CIBIS-II): a randomised trial. Lancet 1999; 353:9-13.

[13.] Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996; 334:1349-55.

[14.] Waagstein F, Bristow MR, Swedberg K, et al. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancet 1993; 342:1441-46.

[15.] Anderson JL, Greenberg B, Boden W, et al. Design of the beta-blocker evaluation survival trial (BEST). Am J Cardiol 1995; 75:1220-23.

[16.] Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Controlled Clin Trials 1996; 17:1-12.

[17.] Petitti DB. Meta-analysis, decision analysis, and cost-effectiveness analysis. 2nd ed. Oxford, England: Oxford University Press, 2000.

[18.] Frishman WH. Carvedilol. N Engl J Med 1999; 339:1759-65.

[19.] Kjekshus, J. Arrhythmias and mortality in congestive heart failure. Am J Cardiol 1990; 65:421-81.

[20.] Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (GESICA): randomised trial of low-dose amiodarone in severe congestive heart failure. Lancet 1994; 344:493-98.

[21.] Eichom EJ. Experience with beta-blockers in heart failure morality trials. Clin Cardiol 1999; 22(supp V):V21-29.

[22.] Krum H. [Beta]-blockers in heart failure: the `new wave' of clinical trials. Drugs 1999; 58:203-10.

[23.] ESC 2000. Beta-blocker Coreg (carvedilol) decreases mortality rates in advanced heart failure. August 29, 2000. Amsterdam, The Netherlands. Doctor's guide. Accessed November 2000. Available at: www.docguide.com/news/content.nsf.

[24.] AHA. Study shows bucindolol does not increase heart failure survival. November 10, 1999. Atlanta, Ga. Doctor's guide. Accessed March 2001. Available at www.pslgroup.com/dg/144af6.htm.

SUSANNE LEE, PHARMD, AND ANNE SPENCER, PHARMD, BCPS Charleston, South Carolina

* Submitted, revised, April 13, 2001.

From the Department of Pharmacy Practice, Medical University of South Carolina, Charleston. Reprint requests should be addressed to Susanne Lee, PharmD, Medical University of South Carolina Drug Information Center, 150 Ashley Avenue, PO Box 250584, Charleston, SC 29425. E-mail: leesj@musc.edu.
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Author:LEE, SUSANNE; SPENCER, ANNE
Publication:Journal of Family Practice
Geographic Code:1USA
Date:Jun 1, 2001
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